Alpha-1 adrenergic receptor antagonists for preventing acute respiratory distress syndrome and death from cytokine storm syndrome.

Vogelstein, Joshua T; Powell, Michael; Koenecke, Allison; Xiong, Ruoxuan; Fischer, Nicole; Huq, Sakibul; Khalafallah, Adham M; Caffo, Brian; Stuart, Elizabeth A; Papadopoulos, Nickolas; Kinzler, Kenneth W; Vogelstein, Bert; Zhou, Shibin; Bettegowda, Chetan; Konig, Maximilian F; Mensh, Brett; Athey, Susan

In severe viral pneumonias, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by a hyperinflammatory reaction ('cytokine storm syndrome') that leads to acute respiratory distress syndrome and death, despite maximal supportive care. Preventing hyperinflammation is key to avoiding these outcomes. We previously demonstrated that alpha-1 adrenergic receptor antagonists ($\alpha$-blockers) can prevent cytokine storm syndrome and death in mice. Here, we conduct a retrospective analysis of patients with acute respiratory distress or pneumonia (n = 13,125 and n = 108,956, respectively) from all causes; patients who were incidentally taking $\alpha$-blockers had a reduced risk of requiring ventilation (by 35% and 16%, respectively), and a reduced risk of being ventilated and dying (by 56% and 20%, respectively), compared to non-users. Beta-adrenergic receptor antagonists had no significant effects. These results highlight the urgent need for prospective trials testing whether prophylactic $\alpha$-blockers improve outcomes in diseases with a prominent hyperinflammatory component such as COVID-19.